Curr Hypertens Rep (2014) 16:452 DOI 10.1007/s11906-014-0452-x
MEDIATORS, MECHANISMS, AND PATHWAYS IN TISSUE INJURY (T FUJITA, SECTION EDITOR)
Oxidative Stress and Organ Damages Sayoko Ogura & Tatsuo Shimosawa
# Springer Science+Business Media New York 2014
Abstract Oxidative stress plays a pivotal role in various pathological conditions, including hypertension, pulmonary hypertension, diabetes, and chronic kidney disease, with high levels of oxidative stress in target organs such as the heart, pancreas, kidney, and lung. Oxidative stress is known to activate multiple intracellular signaling, which induces apoptosis or cell overgrowth, leading to organ dysfunction. As such, targeting oxidative stress is thought to be effective in protecting against organ damage, and measuring oxidative stress status may serve as a biomarker in diverse disease states. Several new intrinsic anti-oxidative or pro-oxidative factors have recently been reported, and are potential new targets. In the present review, we focus on diabetes, pulmonary hypertension, and renal dysfunction, and their relation with new targets – adrenomedullin, oxidized LDL, and mineralocorticoid receptor. Keywords Oxidative stress . Endothelium dysfunction . Antioxidants . Adrenomedullin . LOX-1 . Pulmonary hypertension
Introduction Reactive oxygen species (ROS) is defined as oxygencontaining highly active chemical species having an unpaired electron. Superoxide anion (O2-), hydroxyl radical (HO-), hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and lipid radicals are classified as ROS [1]. It is constitutively produced This article is part of the Topical Collection on Mediators, Mechanisms, and Pathways in Tissue Injury S. Ogura Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan S. Ogura : T. Shimosawa (*) Department of Clinical Laboratory, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e-mail: [email protected]
by mitochondria, peroxisomes, endoplasmic reticulum, and membrane by means of several enzymes. In mitochondria, superoxide anion is produced as a byproduct of ATP production using electron transport chain. Potential ROS-producing enzymes in cellular matrix or membrane include xanthine oxidase, cyclooxygenase, lipoxygenase, NO synthase, heme oxygenase, peroxygenase, heme protein, and or NADH/NADPH oxidase. The roles of these enzymes vary from organ to organ, and multiple enzymes expressed in vasculature tissue are involved,. In the vascular wall, NADH/NADPH oxidase and xanthine oxidase are two major sources of ROS. NADPH oxidase generates superoxide by transferring electrons from NADPH, and NADH/NADPH oxidase is activated by several humoral factors that are closely related to vascular function. Angiotensin II, thrombin, platelet-derived growth factor (PDGF), and TNF have been widely studied [2–4]. Xanthine oxidase not only catalyzes and oxidizes hypoxanthine and xanthine, but also reacts with Snitrosothiol to produce several ROS [5] as well as NO. eNOS, which is a cytochrome P450 reductase-like enzyme, is an important source of ROS in vascular endothelial cells. eNOS utilizes tetrahydrobiopterin (BH4) to produce NO from Larginine, and BH4/L-arginine-deficient eNOS is uncoupled and produces O2- or H2O2.
Reduction of Oxidative Stress and Related Organ Damage ROS status is balanced by the above-mentioned ROSproducing pathways and antioxidants. Superoxide dismutase (SOD) catalyzes the dismutation of O2- into H2O2. Cu-Zn SOD, Mn-SOD, and extracellular SOD are isoforms of SOD, and they localize in the cellular matrix, mitochondria, and extracellular fluid, respectively. H2O2 itself does not have an unpaired electron and is not a free radical, but reacts with Fe3+ via the Fenton reaction to produce hydroxyl radicals (HO-), which are chemically highly reactive. H2O2 is reduced to H2O and O2 by either catalase or glutathione peroxidase (GPx) [1].
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There are several targets as means of reducing ROS levels to protect against organ damage. They include preventing the production of ROS, scavenging ROS as quickly as possible, replacing the damaged organ, and inducing protective function with proper timing and proper localization. Scavengers include the above-mentioned intrinsic antioxidants, and there have been numerous studies on exogenous antioxidants. Vitamins C and E, folate, beta-carotene, and catechin have also been studied extensively. Recent reports have demonstrated antioxidant properties among the pleiotropic effects of cholesterol-lowering drugs probucol and statins [6]. There have been some reports that the exogenous ROS scavengers are effective in preventing cardiovascular events, although this remains controversial [7]. Preventing the production of ROS has the greatest potential to prevent organ damage. However, ROS produced by leukocytes plays an important protective role against infection, and therefore it is necessary to induce ROS-inhibiting signals at the proper time and in the proper organ.
Induction of Cellular Signaling by ROS ROS activates intracellular signaling both non-genomically and genomically. Activation of Ca2+ signal, tyrosine kinases, or mitogen-activated protein kinases (MAPK) are nongenomic actions, while increased expression of MCP-1, VCAM-1, ICAM-1, and atherogenic genes occur via genomic activation of NF-kappa B. Among these target molecules, cJNK and p38 MAPK are classified as members of the stressactivated protein kinase family (SAPK), and lead to pathologic cell proliferation or apoptosis. While ROS is known to cause cellular dysfunction through multiple mechanisms, including cell proliferation, hypertrophy, and apoptosis [8], it still remains to be elucidated in what conditions ROS induces cell overgrowth or apoptosis.
Possible Targets of ROS Regulation Oxidized LDL and its Receptor LOX-1 ROS is known to inhibit endothelial cell migration, affecting endothelial function both directly and in coordination with other factors. One such factor is oxidized LDL, which is produced by oxidation of low-density lipoprotein (LDL) caused by peroxy radicals and free radical chain reactions. The sources of ROS include leukocytes, macrophages, and endothelial cells, as well as vascular smooth muscle cells. Oxidized LDL increases MCP-1 secretion in endothelial cells and further induces monocyte and macrophage infiltration into the vasculature [9]. Infiltrated macrophages migrate into endothelial cells via scavenger receptors and form foam cells.
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In addition, oxidized LDL promotes endothelial cell apoptosis and aggravates its dysfunction [10]. These changes are typical pathological findings in atherosclerotic lesions. Lectin-like oxidized low-density lipoprotein receptor (LOX-1), a specific receptor for oxidized LDL in endothelial cells, is regulated by oxidative stress [11, 12] Oxidized LDL induces ROS via LOX-1, thereby perpetuating the cycle among ROS, LDL, oxidized LDL, and LOX-1. Cellular and organ damage by oxidized LDL-induced ROS is not limited to endothelial cells, but also occurs from cardiomyocyte remodeling after ischemia or inflammation and fibrosis in the kidney [13]. Adrenomedullin Adrenomedullin (AM) was identified by Kitamura in 1993 as a potent vasodilating peptide [14], and studies in AMdeficient mice models revealed its intrinsic antioxidant effects. High levels of 8-iso-prostaglandin F2 excretion, which is a marker of oxidative stress, were present in AM-deficient mice,, and angiotensin II plus salt loading induced local production of ROS in the heart and marked peri-coronary fibrosis and narrowing, independent of blood pressure [15]. In another AM knockout mice model, cuff-induced vascular damage was reduced by topical administration of AM via viral vector, and this effect occurred in parallel with reduction of ROS [16]. These models correlated closely with local and systemic renin-angiotensin system activation, which is a strong inducer of NADPH oxidase and oxidative stress. In vitro experiments showed that AM interfered with angiotensin II signaling and inhibited NADPH oxidase activity [17].
Disease and ROS Insulin Resistance The accumulation of ROS impairs insulin signaling at multiple levels [18, 19]. In aged AM-deficient mice, insulin signaling was impaired in the liver and skeletal muscle [19] as a result of reduced phosphorylation of insulin receptor substrate 1 and 2. A recent study using skeletal muscle cell lines of AMdeficient mice found that ROS reduced glucose transporter transcription by altering histone modification (Shimosawa et al., unpublished data). It is assumed that high ROS level impairs insulin signaling, if pancreatic cells can compensate to some extent and secrete high enough insulin and blood glucose level could be kept low. ROS causes not only insulin resistance but also reduces insulin secretion. It is reported that ROS inhibits PDX-1 binding to insulin promoter [20–22] and induction of apoptosis in pancreatic cells [22]. As such, these mechanisms of ROS are triggers for diabetes, and in turn, high glucose status induces
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high oxidative stress [18]. The Amadori rearrangement during glycation of proteins produces both ROS and advanced glycation end-products (AGEs), and AGE binds to its receptor to further produce ROS. At the same time, glycation of SODs attenuates its bioactivity and decreases concentrations of reduced glutathione, and overall scavenging activity is reduced. In sum, diabetes is associated with increased oxidative stress, and it is considered that high oxidative stress aggravates blood glucose control as well as organ damage.
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Ghasemzadeh et al. recently reported the results of a study in 347 patients in which they found that for each 1 % increase in plasma cystine, right ventricular systolic pressure (RVSP) increased by 16 % [32]. High levels of circulating LOX-1 have been reported in patients with chronic thromboembolic pulmonary hypertension [27], which suggests that oxidative stress and LOX-1 are prognostic markers for pulmonary hypertension. Renal Dysfunction and Aldosterone-Mineralocorticoid Receptor Axis
Pulmonary Hypertension Numerous studies have established the relationship between ROS and pulmonary hypertension [23–25]. In rodent model, hypoxic condition is a model for pulmonary hypertension and hypoxia inudces AM transcription in the lung. AM-deficient mice also developed pulmonary hypertension when they were housed in 10 % O2 conditions for three weeks. Pulmonary artery remodeling was prominent in AM-deficient mice as compared to wild-type mice, and ROS production in AM-deficient mice was enhanced as well [26]. Based upon the effect in rodents, studies were conducted to investigate the use of adrenomedullin for pulmonary hypertensions, in which AM was found to have beneficial hemodynamic effects [27]. NADPH oxidase consists of a catalytic unit, gp91phox, and regulatory subunits p47phox, p67phox, and p40phox. The unit gp91phox is further activated by the small GTP-binding protein Rac1. Liu et al. demonstrated that disruption of the murine NOX2 gene completely abolished chronic hypoxiainduced PAH and vascular remodeling [28]. The role of NADPH oxidase in pulmonary vascular beds is still unknown. We investigated LOX-1-overexpression in a mouse model and found that under hypoxic conditions, NADPH oxidase activity was higher in LOX-1 transgenic mice than in wild-type mice. The level of vascular damage and hemodynamic changes were reversed by the NADPH oxidase inhibitor apocynin [29•]. These data suggest that LOX-1 can be activated under hypoxic conditions and that LOX-1 activates NADPH oxidase and aggravates pulmonary hypertension. It has also been reported that mitochondrial superoxide plays an important role in the development of PH [30] and NOX isoforms in the regulation of mitochondrial ROS [31•]. It remains unknown whether LOX-1 activates the mitochondria or whether there is cross-communication between the m i t o c h o n d r i a a n d N O X . We o b s e r v e d t h a t t h e mitochondria-targeted superoxide dismutase mimetic mitoTEMPO affected the status of ROS in hypoxic LOX-1 Tg mice, although it did not attenuate production of ROS and NADPH oxidase activity. We concluded that LOX-1 increased production of ROS by NADPH oxidase but not by the mitochondria (Ogura. S. et al., unpublished data).
In chronic kidney disease, the kidney is exposed to relatively low oxygen status, and the hypoxic condition is aggravated by ischemia. As in the lung, hypoxia in the kidney also induces high levels of ROS via mitochondria pathway and lower scavenging properties. Among constituents of the kidney, podocytes are considered to be target cells linked to proteinuria and ROS. Podocyte underlies glomerulus and its injury and its loss contribute to proteinuria and glomerulosclerosis [33, 34], and moreover, regulates surrounding cells survival. In recent studies, endothelial mitochondrial oxidative stress has been shown to induce podocyte depletion, resulting in glomerulosclerosis [35•]. To protect the kidney from hypoxic conditions, transcription factors such as hypoxia-inducible factor (HIF) or Keap1-NRF complexes upregulates renoprotective factors such as VEGF and glycolytic enzymes [36•]. Humoral factors also play a role in the progression of renal dysfunction in addition to oxidative stress. Long-term aldosterone and salt loading reduces the number of podocytes in the glomerulus, leading to proteinuria and renal damage [37]. Dietary salt has been found to induce oxidative stress in various organs [38, 39], and aldosterone plus salt loading further activates NADPH oxidase and increases ROS [40]. This effect is inhibited by mineralocorticoid receptor antagonists in the kidney, vascular smooth muscle cells, and endothelial cells [41], suggesting that mineralocorticoid receptor activation by aldosterone may accelerate organ damage by increasing ROS. Rac1, a component of NADPH oxidase, can translocate mineralocorticoid receptors into the nucleus independent of aldosterone, and exerts its genomic effects to induce target genes such as Sgk1 [42]. This suggests that oxidative stress can activate mineralocorticoid receptors in organs even when aldosterone levels are low [43, 44]. This hypothesis is already clinically shown in the heart. Local aldosterone level is low in the cardiomyocyte, however, aldosterone blocker possesses the cardioprotective effect in patients with heart failure who are low in circulating aldosterone level but high in ROS level [45]. This large clinical trial’s finding implies that mineralocorticoid receptor blockade may also be effective in renoprotection under clinical conditions with high ROS level such as diabetic nephropathy or chronic kidney disease.
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Conclusions and Future Direction Oxidative stress is associated with various pathological conditions. Homeostatic mechanisms are involved in the production and scavenging of ROS, and the imbalance and differences in status from organ to organ can cause a wide range of pathological conditions. Not all antioxidants have been shown to have beneficial protective effects against ROS. Adrenomedullin, LOX-1, mineralocorticoid receptors, and Rac1 are good candidates for optimizing oxidative balance within the body, and may be used as therapeutic or diagnostic tools for pulmonary hypertension, insulin resistance, or chronic kidney disease. Insulin resistance and mineralocorticoid receptor activationinduced sodium retention and cardiac dysfunction could be a trigger of life-threatening non-communicable disease such as diabetes, hypertension and heart failure. Further research to target oxidative stress can reverse both insulin resistance and mineralocorticoid receptor activity and result in promoting mortality and morbidity.
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12. Acknowledgments This work was supported by JSPS KAKENHI Grant Number 24790863, 26461262. Compliance with Ethics Guidelines Conflict of Interest Sayoko Ogura has received a JSPS KAKENHI Grant Number 24790863, 26461262. Tatsuo Shimosawa has received an honorarium payment from Takeda Pharmaceutical Co., Ltd.
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15. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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References
17.
Papers of particular interest, published recently, have been highlighted as: • Of importance
1.
2.
3.
4.
Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS. Circulation. 2003;108(16):1912–6. doi:10.1161/01.CIR. 0000093660.86242. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74(6):1141–8. Holland JA, Meyer JW, Chang MM, O’Donnell RW, Johnson DK, Ziegler LM. Thrombin stimulated reactive oxygen species production in cultured human endothelial cells. Endothelium. 1998;6(2):113–21. Marumo T, Schini-Kerth VB, Fisslthaler B, Busse R. Plateletderived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells. Circulation. 1997;96(7):2361–7.
18.
19.
20.
21.
22.
Cardillo C, Kilcoyne CM, Cannon 3rd RO, Quyyumi AA, Panza JA. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension. 1997;30(1 Pt 1):57–63. Hermida N, Balligand JL. Low-density lipoprotein-cholesterolinduced endothelial dysfunction and oxidative stress: the role of statins. Antioxid Redox Signal. 2014;20(8):1216–37. doi:10.1089/ ars.2013.5537. Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293(11):1338–47. doi:10.1001/jama.293.11.1338. Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res. 1999;85(8):753–66. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A. 1987;84(9):2995–8. Li D, Yang B, Mehta JL. Ox-LDL induces apoptosis in human coronary artery endothelial cells: role of PKC, PTK, bcl-2, and Fas. Am J Physiol. 1998;275(2 Pt 2):H568–76. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386(6620):73–7. doi:10.1038/386073a0. Nagase M, Ando K, Nagase T, Kaname S, Sawamura T, Fujita T. Redox-sensitive regulation of lox-1 gene expression in vascular endothelium. Biochem Biophys Res Commun. 2001;281(3):720– 5. doi:10.1006/bbrc.2001.4374. Ogura S, Kakino A, Sato Y, Fujita Y, Iwamoto S, Otsui K, et al. Lox-1: the multifunctional receptor underlying cardiovascular dysfunction. Circ J. 2009;73(11):1993–9. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 1993;192(2):553–60. doi:10.1006/bbrc.1993.1451. Shimosawa T, Shibagaki Y, Ishibashi K, Kitamura K, Kangawa K, Kato S, et al. Adrenomedullin, an endogenous peptide, counteracts cardiovascular damage. Circulation. 2002;105(1):106–11. Kawai J, Ando K, Tojo A, Shimosawa T, Takahashi K, Onozato ML, et al. Endogenous adrenomedullin protects against vascular response to injury in mice. Circulation. 2004;109(9):1147–53. doi: 10.1161/01.CIR.0000117231.40057.6D. Liu J, Shimosawa T, Matsui H, Meng F, Supowit SC, DiPette DJ, et al. Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity. Am J Physiol Heart Circ Physiol. 2007;292(4):H1714–21. doi:10.1152/ajpheart. 00486.2006. Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima N, et al. Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia. 2004;47(5):794–805. doi:10.1007/s00125-004-1391-x. Fridlyand LE, Philipson LH. Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes Metab. 2006;8(2):136–45. doi:10.1111/j.1463-1326.2005.00496.x. Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, et al. Glycation-dependent, reactive oxygen speciesmediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest. 1997;99(1):144–50. doi:10.1172/JCI119126. Kaneto H, Xu G, Fujii N, Kim S, Bonner-Weir S, Weir GC. Involvement of c-Jun N-terminal kinase in oxidative stressmediated suppression of insulin gene expression. J Biol Chem. 2002;277(33):30010–8. doi:10.1074/jbc.M202066200. Kawamori D, Kajimoto Y, Kaneto H, Umayahara Y, Fujitani Y, Miyatsuka T, et al. Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through
Curr Hypertens Rep (2014) 16:452
23.
24.
25.
26.
27.
28.
29.•
30.
31.•
32.
33.
activation of c-Jun NH(2)-terminal kinase. Diabetes. 2003;52(12): 2896–904. DeMarco VG, Habibi J, Whaley-Connell AT, Schneider RI, Heller RL, Bosanquet JP, et al. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol. 2008;294(6):H2659–68. doi:10.1152/ajpheart.00953. 2007. Hoshikawa Y, Ono S, Suzuki S, Tanita T, Chida M, Song C, et al. Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol. 2001;90(4):1299–306. Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, et al. Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med. 2004;169(6):764–9. doi:10.1164/rccm. 200301-147OC. Matsui H, Shimosawa T, Itakura K, Guanqun X, Ando K, Fujita T. Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia. Circulation. 2004;109(18):2246–51. doi: 10.1161/01.CIR.0000127950.13380.FD. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Oya H, Kyotani S, et al. Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension. Heart. 2000;84(6): 653–8. Liu JQ, Zelko IN, Erbynn EM, Sham JS, Folz RJ. Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol. 2006;290(1): L2–10. doi:10.1152/ajplung.00135.2005. Ogura S, Shimosawa T, Mu S, Sonobe T, Kawakami-Mori F, Wang H, et al. Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor. Am J Physiol Heart Circ Physiol. 2013;305(2):H155–62. doi: 10.1152/ajpheart.00169.2012. In this paper, the role of a receptor of oxidized LDL receptor in pulmonary hypertension is revealed. When the receptor is overexpressed and mice were subjected to hypoxic condition, they developed severe pumonary hypertension, together with increasing oxidative stress via NADPH oxidase activation. This suggests that a receptor for oxidized LDL is one of the receptors to transmit ROS signaling. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121(24): 2661–71. doi:10.1161/CIRCULATIONAHA.109.916098. Dikalov SI, Nazarewicz RR, Bikineyeva A, Hilenski L, Lassegue B, Griendling KK, et al. Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. Antioxid Redox Signal. 2014;20(2):281–94. doi: 10.1089/ars.2012.4918. It has been reported that angiotensin II is an activator for NADPH oxidase and increases ROS in variety of organs. This paper reports that angiotensin II can activate mitochondrial ROS by activating NOX2, mitochondrial K channel. Moreover, mitochondria-derived ROS can further activate cytoplasmic c-Src to activate NADPH oxidase and therefore increase ROS in feed-forward fashion. Ghasemzadeh N, Patel RS, Eapen DJ, Veledar E, Al Kassem H, Manocha P, et al. Oxidative stress is associated with increased pulmonary artery systolic pressure in humans. Hypertension. 2014. doi:10.1161/HYPERTENSIONAHA.113.02360. Kriz W. Glomerular diseases: podocyte hypertrophy mismatch and glomerular disease. Nat Rev Nephrol. 2012;8(11):618–9. doi:10. 1038/nrneph.2012.198.
Page 5 of 5, 452 34.
35.•
36.•
37.
38.
39.
40.
41.
42.
43.
44.
45.
Carney EF. Glomerular disease: Albuminuria inhibits podocyte regeneration. Nat Rev Nephrol. 2013;9(10):554. doi:10.1038/ nrneph.2013.159. Daehn I, Casalena G, Zhang T, Shi S, Fenninger F, Barasch N, et al. Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J Clin Invest. 2014;124(4):1608–21. doi:10.1172/JCI71195. This paper reported that reciprocal crosstalk between endothelial cells and podocyte in the kidney plays a pivotal role in glomerular injury. The factors that mediate the crosstalk are TGF beta and endothelin in podocyte and subsequent activation of mitochondrial ROS production in endothelial cells. The data are confirmed both in rodent model and human samples. Targeting mitochondrial ROS can prevent renal damage. Miyata T, Takizawa S, van Ypersele de Strihou C. Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets. Am J Physiol Cell Physiol. 2011;300(2):C226–31. doi:10.1152/ajpcell.00430.2010. This paper is a review on the relationship between hypoxia and ROS in terms of HIF activity and Nrf -1 activity. HIF-1alpha activation can reduce ROS. HIF-1alpha is degradated when it is hydroxylated by PHD. Nrf is also protective against ROS and is degradated by Keap-1. This review includes possible therapeutic compounds that inhibit PHD or increase Nrf-1. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49(2):355–64. doi:10.1161/01.HYP. 0000255636.11931.a2. Ogihara T, Asano T, Ando K, Chiba Y, Sekine N, Sakoda H, et al. Insulin resistance with enhanced insulin signaling in high-salt dietfed rats. Diabetes. 2001;50(3):573–83. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446): 518–22. doi:10.1038/nature11868. Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S, et al. Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/ salt-induced hypertensive rats. Hypertension. 2004;43(4):841–8. doi:10.1161/01.HYP.0000118519.66430.22. Mutoh A, Isshiki M, Fujita T. Aldosterone enhances ligandstimulated nitric oxide production in endothelial cells. Hypertens Res. 2008;31(9):1811–20. doi:10.1291/hypres.31.1811. Shibata S, Mu S, Kawarazaki H, Muraoka K, Ishizawa K, Yoshida S, et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121(8):3233–43. doi:10.1172/JCI43124. Wang H, Shimosawa T, Matsui H, Kaneko T, Ogura S, Uetake Y, et al. Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions. J Hypertens. 2008;26(7):1453–62. doi:10.1097/HJH. 0b013e328300a232. Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, et al. Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension. 2012;59(2):500–6. doi:10.1161/ HYPERTENSIONAHA.111.185520. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med. 1999;341(10):709–17. doi:10.1056/ NEJM199909023411001.
MEDIATORS, MECHANISMS, AND PATHWAYS IN TISSUE INJURY (T FUJITA, SECTION EDITOR)
Oxidative Stress and Organ Damages Sayoko Ogura & Tatsuo Shimosawa
# Springer Science+Business Media New York 2014
Abstract Oxidative stress plays a pivotal role in various pathological conditions, including hypertension, pulmonary hypertension, diabetes, and chronic kidney disease, with high levels of oxidative stress in target organs such as the heart, pancreas, kidney, and lung. Oxidative stress is known to activate multiple intracellular signaling, which induces apoptosis or cell overgrowth, leading to organ dysfunction. As such, targeting oxidative stress is thought to be effective in protecting against organ damage, and measuring oxidative stress status may serve as a biomarker in diverse disease states. Several new intrinsic anti-oxidative or pro-oxidative factors have recently been reported, and are potential new targets. In the present review, we focus on diabetes, pulmonary hypertension, and renal dysfunction, and their relation with new targets – adrenomedullin, oxidized LDL, and mineralocorticoid receptor. Keywords Oxidative stress . Endothelium dysfunction . Antioxidants . Adrenomedullin . LOX-1 . Pulmonary hypertension
Introduction Reactive oxygen species (ROS) is defined as oxygencontaining highly active chemical species having an unpaired electron. Superoxide anion (O2-), hydroxyl radical (HO-), hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and lipid radicals are classified as ROS [1]. It is constitutively produced This article is part of the Topical Collection on Mediators, Mechanisms, and Pathways in Tissue Injury S. Ogura Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan S. Ogura : T. Shimosawa (*) Department of Clinical Laboratory, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e-mail: [email protected]
by mitochondria, peroxisomes, endoplasmic reticulum, and membrane by means of several enzymes. In mitochondria, superoxide anion is produced as a byproduct of ATP production using electron transport chain. Potential ROS-producing enzymes in cellular matrix or membrane include xanthine oxidase, cyclooxygenase, lipoxygenase, NO synthase, heme oxygenase, peroxygenase, heme protein, and or NADH/NADPH oxidase. The roles of these enzymes vary from organ to organ, and multiple enzymes expressed in vasculature tissue are involved,. In the vascular wall, NADH/NADPH oxidase and xanthine oxidase are two major sources of ROS. NADPH oxidase generates superoxide by transferring electrons from NADPH, and NADH/NADPH oxidase is activated by several humoral factors that are closely related to vascular function. Angiotensin II, thrombin, platelet-derived growth factor (PDGF), and TNF have been widely studied [2–4]. Xanthine oxidase not only catalyzes and oxidizes hypoxanthine and xanthine, but also reacts with Snitrosothiol to produce several ROS [5] as well as NO. eNOS, which is a cytochrome P450 reductase-like enzyme, is an important source of ROS in vascular endothelial cells. eNOS utilizes tetrahydrobiopterin (BH4) to produce NO from Larginine, and BH4/L-arginine-deficient eNOS is uncoupled and produces O2- or H2O2.
Reduction of Oxidative Stress and Related Organ Damage ROS status is balanced by the above-mentioned ROSproducing pathways and antioxidants. Superoxide dismutase (SOD) catalyzes the dismutation of O2- into H2O2. Cu-Zn SOD, Mn-SOD, and extracellular SOD are isoforms of SOD, and they localize in the cellular matrix, mitochondria, and extracellular fluid, respectively. H2O2 itself does not have an unpaired electron and is not a free radical, but reacts with Fe3+ via the Fenton reaction to produce hydroxyl radicals (HO-), which are chemically highly reactive. H2O2 is reduced to H2O and O2 by either catalase or glutathione peroxidase (GPx) [1].
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There are several targets as means of reducing ROS levels to protect against organ damage. They include preventing the production of ROS, scavenging ROS as quickly as possible, replacing the damaged organ, and inducing protective function with proper timing and proper localization. Scavengers include the above-mentioned intrinsic antioxidants, and there have been numerous studies on exogenous antioxidants. Vitamins C and E, folate, beta-carotene, and catechin have also been studied extensively. Recent reports have demonstrated antioxidant properties among the pleiotropic effects of cholesterol-lowering drugs probucol and statins [6]. There have been some reports that the exogenous ROS scavengers are effective in preventing cardiovascular events, although this remains controversial [7]. Preventing the production of ROS has the greatest potential to prevent organ damage. However, ROS produced by leukocytes plays an important protective role against infection, and therefore it is necessary to induce ROS-inhibiting signals at the proper time and in the proper organ.
Induction of Cellular Signaling by ROS ROS activates intracellular signaling both non-genomically and genomically. Activation of Ca2+ signal, tyrosine kinases, or mitogen-activated protein kinases (MAPK) are nongenomic actions, while increased expression of MCP-1, VCAM-1, ICAM-1, and atherogenic genes occur via genomic activation of NF-kappa B. Among these target molecules, cJNK and p38 MAPK are classified as members of the stressactivated protein kinase family (SAPK), and lead to pathologic cell proliferation or apoptosis. While ROS is known to cause cellular dysfunction through multiple mechanisms, including cell proliferation, hypertrophy, and apoptosis [8], it still remains to be elucidated in what conditions ROS induces cell overgrowth or apoptosis.
Possible Targets of ROS Regulation Oxidized LDL and its Receptor LOX-1 ROS is known to inhibit endothelial cell migration, affecting endothelial function both directly and in coordination with other factors. One such factor is oxidized LDL, which is produced by oxidation of low-density lipoprotein (LDL) caused by peroxy radicals and free radical chain reactions. The sources of ROS include leukocytes, macrophages, and endothelial cells, as well as vascular smooth muscle cells. Oxidized LDL increases MCP-1 secretion in endothelial cells and further induces monocyte and macrophage infiltration into the vasculature [9]. Infiltrated macrophages migrate into endothelial cells via scavenger receptors and form foam cells.
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In addition, oxidized LDL promotes endothelial cell apoptosis and aggravates its dysfunction [10]. These changes are typical pathological findings in atherosclerotic lesions. Lectin-like oxidized low-density lipoprotein receptor (LOX-1), a specific receptor for oxidized LDL in endothelial cells, is regulated by oxidative stress [11, 12] Oxidized LDL induces ROS via LOX-1, thereby perpetuating the cycle among ROS, LDL, oxidized LDL, and LOX-1. Cellular and organ damage by oxidized LDL-induced ROS is not limited to endothelial cells, but also occurs from cardiomyocyte remodeling after ischemia or inflammation and fibrosis in the kidney [13]. Adrenomedullin Adrenomedullin (AM) was identified by Kitamura in 1993 as a potent vasodilating peptide [14], and studies in AMdeficient mice models revealed its intrinsic antioxidant effects. High levels of 8-iso-prostaglandin F2 excretion, which is a marker of oxidative stress, were present in AM-deficient mice,, and angiotensin II plus salt loading induced local production of ROS in the heart and marked peri-coronary fibrosis and narrowing, independent of blood pressure [15]. In another AM knockout mice model, cuff-induced vascular damage was reduced by topical administration of AM via viral vector, and this effect occurred in parallel with reduction of ROS [16]. These models correlated closely with local and systemic renin-angiotensin system activation, which is a strong inducer of NADPH oxidase and oxidative stress. In vitro experiments showed that AM interfered with angiotensin II signaling and inhibited NADPH oxidase activity [17].
Disease and ROS Insulin Resistance The accumulation of ROS impairs insulin signaling at multiple levels [18, 19]. In aged AM-deficient mice, insulin signaling was impaired in the liver and skeletal muscle [19] as a result of reduced phosphorylation of insulin receptor substrate 1 and 2. A recent study using skeletal muscle cell lines of AMdeficient mice found that ROS reduced glucose transporter transcription by altering histone modification (Shimosawa et al., unpublished data). It is assumed that high ROS level impairs insulin signaling, if pancreatic cells can compensate to some extent and secrete high enough insulin and blood glucose level could be kept low. ROS causes not only insulin resistance but also reduces insulin secretion. It is reported that ROS inhibits PDX-1 binding to insulin promoter [20–22] and induction of apoptosis in pancreatic cells [22]. As such, these mechanisms of ROS are triggers for diabetes, and in turn, high glucose status induces
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high oxidative stress [18]. The Amadori rearrangement during glycation of proteins produces both ROS and advanced glycation end-products (AGEs), and AGE binds to its receptor to further produce ROS. At the same time, glycation of SODs attenuates its bioactivity and decreases concentrations of reduced glutathione, and overall scavenging activity is reduced. In sum, diabetes is associated with increased oxidative stress, and it is considered that high oxidative stress aggravates blood glucose control as well as organ damage.
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Ghasemzadeh et al. recently reported the results of a study in 347 patients in which they found that for each 1 % increase in plasma cystine, right ventricular systolic pressure (RVSP) increased by 16 % [32]. High levels of circulating LOX-1 have been reported in patients with chronic thromboembolic pulmonary hypertension [27], which suggests that oxidative stress and LOX-1 are prognostic markers for pulmonary hypertension. Renal Dysfunction and Aldosterone-Mineralocorticoid Receptor Axis
Pulmonary Hypertension Numerous studies have established the relationship between ROS and pulmonary hypertension [23–25]. In rodent model, hypoxic condition is a model for pulmonary hypertension and hypoxia inudces AM transcription in the lung. AM-deficient mice also developed pulmonary hypertension when they were housed in 10 % O2 conditions for three weeks. Pulmonary artery remodeling was prominent in AM-deficient mice as compared to wild-type mice, and ROS production in AM-deficient mice was enhanced as well [26]. Based upon the effect in rodents, studies were conducted to investigate the use of adrenomedullin for pulmonary hypertensions, in which AM was found to have beneficial hemodynamic effects [27]. NADPH oxidase consists of a catalytic unit, gp91phox, and regulatory subunits p47phox, p67phox, and p40phox. The unit gp91phox is further activated by the small GTP-binding protein Rac1. Liu et al. demonstrated that disruption of the murine NOX2 gene completely abolished chronic hypoxiainduced PAH and vascular remodeling [28]. The role of NADPH oxidase in pulmonary vascular beds is still unknown. We investigated LOX-1-overexpression in a mouse model and found that under hypoxic conditions, NADPH oxidase activity was higher in LOX-1 transgenic mice than in wild-type mice. The level of vascular damage and hemodynamic changes were reversed by the NADPH oxidase inhibitor apocynin [29•]. These data suggest that LOX-1 can be activated under hypoxic conditions and that LOX-1 activates NADPH oxidase and aggravates pulmonary hypertension. It has also been reported that mitochondrial superoxide plays an important role in the development of PH [30] and NOX isoforms in the regulation of mitochondrial ROS [31•]. It remains unknown whether LOX-1 activates the mitochondria or whether there is cross-communication between the m i t o c h o n d r i a a n d N O X . We o b s e r v e d t h a t t h e mitochondria-targeted superoxide dismutase mimetic mitoTEMPO affected the status of ROS in hypoxic LOX-1 Tg mice, although it did not attenuate production of ROS and NADPH oxidase activity. We concluded that LOX-1 increased production of ROS by NADPH oxidase but not by the mitochondria (Ogura. S. et al., unpublished data).
In chronic kidney disease, the kidney is exposed to relatively low oxygen status, and the hypoxic condition is aggravated by ischemia. As in the lung, hypoxia in the kidney also induces high levels of ROS via mitochondria pathway and lower scavenging properties. Among constituents of the kidney, podocytes are considered to be target cells linked to proteinuria and ROS. Podocyte underlies glomerulus and its injury and its loss contribute to proteinuria and glomerulosclerosis [33, 34], and moreover, regulates surrounding cells survival. In recent studies, endothelial mitochondrial oxidative stress has been shown to induce podocyte depletion, resulting in glomerulosclerosis [35•]. To protect the kidney from hypoxic conditions, transcription factors such as hypoxia-inducible factor (HIF) or Keap1-NRF complexes upregulates renoprotective factors such as VEGF and glycolytic enzymes [36•]. Humoral factors also play a role in the progression of renal dysfunction in addition to oxidative stress. Long-term aldosterone and salt loading reduces the number of podocytes in the glomerulus, leading to proteinuria and renal damage [37]. Dietary salt has been found to induce oxidative stress in various organs [38, 39], and aldosterone plus salt loading further activates NADPH oxidase and increases ROS [40]. This effect is inhibited by mineralocorticoid receptor antagonists in the kidney, vascular smooth muscle cells, and endothelial cells [41], suggesting that mineralocorticoid receptor activation by aldosterone may accelerate organ damage by increasing ROS. Rac1, a component of NADPH oxidase, can translocate mineralocorticoid receptors into the nucleus independent of aldosterone, and exerts its genomic effects to induce target genes such as Sgk1 [42]. This suggests that oxidative stress can activate mineralocorticoid receptors in organs even when aldosterone levels are low [43, 44]. This hypothesis is already clinically shown in the heart. Local aldosterone level is low in the cardiomyocyte, however, aldosterone blocker possesses the cardioprotective effect in patients with heart failure who are low in circulating aldosterone level but high in ROS level [45]. This large clinical trial’s finding implies that mineralocorticoid receptor blockade may also be effective in renoprotection under clinical conditions with high ROS level such as diabetic nephropathy or chronic kidney disease.
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Conclusions and Future Direction Oxidative stress is associated with various pathological conditions. Homeostatic mechanisms are involved in the production and scavenging of ROS, and the imbalance and differences in status from organ to organ can cause a wide range of pathological conditions. Not all antioxidants have been shown to have beneficial protective effects against ROS. Adrenomedullin, LOX-1, mineralocorticoid receptors, and Rac1 are good candidates for optimizing oxidative balance within the body, and may be used as therapeutic or diagnostic tools for pulmonary hypertension, insulin resistance, or chronic kidney disease. Insulin resistance and mineralocorticoid receptor activationinduced sodium retention and cardiac dysfunction could be a trigger of life-threatening non-communicable disease such as diabetes, hypertension and heart failure. Further research to target oxidative stress can reverse both insulin resistance and mineralocorticoid receptor activity and result in promoting mortality and morbidity.
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12. Acknowledgments This work was supported by JSPS KAKENHI Grant Number 24790863, 26461262. Compliance with Ethics Guidelines Conflict of Interest Sayoko Ogura has received a JSPS KAKENHI Grant Number 24790863, 26461262. Tatsuo Shimosawa has received an honorarium payment from Takeda Pharmaceutical Co., Ltd.
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15. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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References
17.
Papers of particular interest, published recently, have been highlighted as: • Of importance
1.
2.
3.
4.
Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS. Circulation. 2003;108(16):1912–6. doi:10.1161/01.CIR. 0000093660.86242. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74(6):1141–8. Holland JA, Meyer JW, Chang MM, O’Donnell RW, Johnson DK, Ziegler LM. Thrombin stimulated reactive oxygen species production in cultured human endothelial cells. Endothelium. 1998;6(2):113–21. Marumo T, Schini-Kerth VB, Fisslthaler B, Busse R. Plateletderived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells. Circulation. 1997;96(7):2361–7.
18.
19.
20.
21.
22.
Cardillo C, Kilcoyne CM, Cannon 3rd RO, Quyyumi AA, Panza JA. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension. 1997;30(1 Pt 1):57–63. Hermida N, Balligand JL. Low-density lipoprotein-cholesterolinduced endothelial dysfunction and oxidative stress: the role of statins. Antioxid Redox Signal. 2014;20(8):1216–37. doi:10.1089/ ars.2013.5537. Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293(11):1338–47. doi:10.1001/jama.293.11.1338. Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res. 1999;85(8):753–66. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A. 1987;84(9):2995–8. Li D, Yang B, Mehta JL. Ox-LDL induces apoptosis in human coronary artery endothelial cells: role of PKC, PTK, bcl-2, and Fas. Am J Physiol. 1998;275(2 Pt 2):H568–76. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386(6620):73–7. doi:10.1038/386073a0. Nagase M, Ando K, Nagase T, Kaname S, Sawamura T, Fujita T. Redox-sensitive regulation of lox-1 gene expression in vascular endothelium. Biochem Biophys Res Commun. 2001;281(3):720– 5. doi:10.1006/bbrc.2001.4374. Ogura S, Kakino A, Sato Y, Fujita Y, Iwamoto S, Otsui K, et al. Lox-1: the multifunctional receptor underlying cardiovascular dysfunction. Circ J. 2009;73(11):1993–9. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 1993;192(2):553–60. doi:10.1006/bbrc.1993.1451. Shimosawa T, Shibagaki Y, Ishibashi K, Kitamura K, Kangawa K, Kato S, et al. Adrenomedullin, an endogenous peptide, counteracts cardiovascular damage. Circulation. 2002;105(1):106–11. Kawai J, Ando K, Tojo A, Shimosawa T, Takahashi K, Onozato ML, et al. Endogenous adrenomedullin protects against vascular response to injury in mice. Circulation. 2004;109(9):1147–53. doi: 10.1161/01.CIR.0000117231.40057.6D. Liu J, Shimosawa T, Matsui H, Meng F, Supowit SC, DiPette DJ, et al. Adrenomedullin inhibits angiotensin II-induced oxidative stress via Csk-mediated inhibition of Src activity. Am J Physiol Heart Circ Physiol. 2007;292(4):H1714–21. doi:10.1152/ajpheart. 00486.2006. Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima N, et al. Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia. 2004;47(5):794–805. doi:10.1007/s00125-004-1391-x. Fridlyand LE, Philipson LH. Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes Metab. 2006;8(2):136–45. doi:10.1111/j.1463-1326.2005.00496.x. Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, et al. Glycation-dependent, reactive oxygen speciesmediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest. 1997;99(1):144–50. doi:10.1172/JCI119126. Kaneto H, Xu G, Fujii N, Kim S, Bonner-Weir S, Weir GC. Involvement of c-Jun N-terminal kinase in oxidative stressmediated suppression of insulin gene expression. J Biol Chem. 2002;277(33):30010–8. doi:10.1074/jbc.M202066200. Kawamori D, Kajimoto Y, Kaneto H, Umayahara Y, Fujitani Y, Miyatsuka T, et al. Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through
Curr Hypertens Rep (2014) 16:452
23.
24.
25.
26.
27.
28.
29.•
30.
31.•
32.
33.
activation of c-Jun NH(2)-terminal kinase. Diabetes. 2003;52(12): 2896–904. DeMarco VG, Habibi J, Whaley-Connell AT, Schneider RI, Heller RL, Bosanquet JP, et al. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol. 2008;294(6):H2659–68. doi:10.1152/ajpheart.00953. 2007. Hoshikawa Y, Ono S, Suzuki S, Tanita T, Chida M, Song C, et al. Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol. 2001;90(4):1299–306. Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, et al. Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med. 2004;169(6):764–9. doi:10.1164/rccm. 200301-147OC. Matsui H, Shimosawa T, Itakura K, Guanqun X, Ando K, Fujita T. Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia. Circulation. 2004;109(18):2246–51. doi: 10.1161/01.CIR.0000127950.13380.FD. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Oya H, Kyotani S, et al. Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension. Heart. 2000;84(6): 653–8. Liu JQ, Zelko IN, Erbynn EM, Sham JS, Folz RJ. Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol. 2006;290(1): L2–10. doi:10.1152/ajplung.00135.2005. Ogura S, Shimosawa T, Mu S, Sonobe T, Kawakami-Mori F, Wang H, et al. Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor. Am J Physiol Heart Circ Physiol. 2013;305(2):H155–62. doi: 10.1152/ajpheart.00169.2012. In this paper, the role of a receptor of oxidized LDL receptor in pulmonary hypertension is revealed. When the receptor is overexpressed and mice were subjected to hypoxic condition, they developed severe pumonary hypertension, together with increasing oxidative stress via NADPH oxidase activation. This suggests that a receptor for oxidized LDL is one of the receptors to transmit ROS signaling. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121(24): 2661–71. doi:10.1161/CIRCULATIONAHA.109.916098. Dikalov SI, Nazarewicz RR, Bikineyeva A, Hilenski L, Lassegue B, Griendling KK, et al. Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension. Antioxid Redox Signal. 2014;20(2):281–94. doi: 10.1089/ars.2012.4918. It has been reported that angiotensin II is an activator for NADPH oxidase and increases ROS in variety of organs. This paper reports that angiotensin II can activate mitochondrial ROS by activating NOX2, mitochondrial K channel. Moreover, mitochondria-derived ROS can further activate cytoplasmic c-Src to activate NADPH oxidase and therefore increase ROS in feed-forward fashion. Ghasemzadeh N, Patel RS, Eapen DJ, Veledar E, Al Kassem H, Manocha P, et al. Oxidative stress is associated with increased pulmonary artery systolic pressure in humans. Hypertension. 2014. doi:10.1161/HYPERTENSIONAHA.113.02360. Kriz W. Glomerular diseases: podocyte hypertrophy mismatch and glomerular disease. Nat Rev Nephrol. 2012;8(11):618–9. doi:10. 1038/nrneph.2012.198.
Page 5 of 5, 452 34.
35.•
36.•
37.
38.
39.
40.
41.
42.
43.
44.
45.
Carney EF. Glomerular disease: Albuminuria inhibits podocyte regeneration. Nat Rev Nephrol. 2013;9(10):554. doi:10.1038/ nrneph.2013.159. Daehn I, Casalena G, Zhang T, Shi S, Fenninger F, Barasch N, et al. Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J Clin Invest. 2014;124(4):1608–21. doi:10.1172/JCI71195. This paper reported that reciprocal crosstalk between endothelial cells and podocyte in the kidney plays a pivotal role in glomerular injury. The factors that mediate the crosstalk are TGF beta and endothelin in podocyte and subsequent activation of mitochondrial ROS production in endothelial cells. The data are confirmed both in rodent model and human samples. Targeting mitochondrial ROS can prevent renal damage. Miyata T, Takizawa S, van Ypersele de Strihou C. Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets. Am J Physiol Cell Physiol. 2011;300(2):C226–31. doi:10.1152/ajpcell.00430.2010. This paper is a review on the relationship between hypoxia and ROS in terms of HIF activity and Nrf -1 activity. HIF-1alpha activation can reduce ROS. HIF-1alpha is degradated when it is hydroxylated by PHD. Nrf is also protective against ROS and is degradated by Keap-1. This review includes possible therapeutic compounds that inhibit PHD or increase Nrf-1. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007;49(2):355–64. doi:10.1161/01.HYP. 0000255636.11931.a2. Ogihara T, Asano T, Ando K, Chiba Y, Sekine N, Sakoda H, et al. Insulin resistance with enhanced insulin signaling in high-salt dietfed rats. Diabetes. 2001;50(3):573–83. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446): 518–22. doi:10.1038/nature11868. Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S, et al. Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/ salt-induced hypertensive rats. Hypertension. 2004;43(4):841–8. doi:10.1161/01.HYP.0000118519.66430.22. Mutoh A, Isshiki M, Fujita T. Aldosterone enhances ligandstimulated nitric oxide production in endothelial cells. Hypertens Res. 2008;31(9):1811–20. doi:10.1291/hypres.31.1811. Shibata S, Mu S, Kawarazaki H, Muraoka K, Ishizawa K, Yoshida S, et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121(8):3233–43. doi:10.1172/JCI43124. Wang H, Shimosawa T, Matsui H, Kaneko T, Ogura S, Uetake Y, et al. Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions. J Hypertens. 2008;26(7):1453–62. doi:10.1097/HJH. 0b013e328300a232. Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, et al. Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension. 2012;59(2):500–6. doi:10.1161/ HYPERTENSIONAHA.111.185520. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med. 1999;341(10):709–17. doi:10.1056/ NEJM199909023411001.
